1. Field of the Invention
The present invention relates to a method for producing porous polymer materials. In particular, the invention involves the formation of porous polymer materials used in biotechnology.
2. Description of the Prior Art
In recent years, the field of tissue engineering has evolved from the integration of biomedical material and the cultural technology of cell tissues followed by the continuous progress in biotechnology. One of the critical aspects in tissue engineering is to develop degradable porous substrate. To replace defective tissue, new cell tissues are adhered onto a porous polymer substrate, and new tissues grow in the three dimensional structure of the substrate. After cell tissues are cultivated, the porous material degrades gradually and is fully absorbed and replaced. Finally, the composite substrate comprising the implanted cells and polymer material replaces the original defects and become normal tissue. Since it is required to grow cells in the polymer material, the polymer material must be:
1. absorbable and degradable
2. highly and three-dimensionally porous
3. appropriately apertured
4. interconnectedly voided
Presently, the absorbable polymer mostly valued by researchers is biodegradable polymer material, such as polyglycolic acid (PGA), polylactic acid (PLA), poly glycolide-co-lactide acid (PLGA), polycaprolactone, polydioxanone and polyorthoester. These materials can be degraded into small molecule segments and are released from the subject by metabolism. As a result, degraded products do not stay in the human body.
Following recent developments in tissue engineering, a number of processes for producing biodegradable porous polymer substrate have been proposed. However, there has not been a continuous process able to produce a multi-layer porous polymer material of different composition, with different apertures and porosities.
In current tissue engineering, a small part of healthy tissue of the patient or donor is collected and wholly cultivated in vitro, followed by implantation onto a degradable porous substrate. The implanted cell tissue adheres onto the three dimensional structure of the substrate and grows in it. After the tissue is cultivated, it is then implanted back to the patient as required. Arrangement and patterning of the cultivated tissues is determined by the structure of the three dimensional porous substrate. Current methods for producing porous substrate can produce a substrate with only one porosity or comprising only one type of material. However, human tissues are continuous and have multi-layered structures, which comprise substrates with different densities among tissues and different components. Hence, it is critical to develop a porous substrate with adjustable porosity, and comprising various compositions.
At the moment, methods for producing porous polymer material are:
1. solution casting
2. solvent-casting particulate leaching
3. gel casting
4. gas saturation
5. phase separation
6. bonded fiber
7. particle sintering
Though the above methods produce various kinds of substrates with different porosities or apertures, they cannot continuously produce multi-layer substrates made from different material, and at the same time, have different porosities and apertures. As disclosed in U.S. Pat. No. 5,514,378, solvent-casting particulate leaching is used to produce two dimensional thin films of polymer material. Those thin films are then stacked to form a multi-layer three dimensional substrate. However, this method is limited due to problems such as irregular distribution of salt granules and polymer caused by differences in densities. Consequently, salt granules can be fully covered by polymer and organic solvents are likely to remain inside the substrate. Also, the thickness of produced substrate is limited to about 2000 xcexcm. As a result, substrates must be stacked to produce thicker or three dimensional substrates. Although substrates with different apertures or porosities can be obtained by adding salt granules of different particle sizes in different ratios, followed by stacking layers of substrates as required to form three dimensional substrates, the thickness of a single layer of substrate is limited, and solvent is required to cohere various layers together so as to form interconnecting apertures. By doing so, it creates problems by closing part of the apertures in different layers as they dissolve in solvent. This is not a continuous process as required. Furthermore, stacking layers by hand is necessary, which further adds complexity to the process. In phase separation, patterning of voids is controlled by the arrangement of condensed crystals. However, the technology for controlling the types of condensed crystal, particle size, uniformity and arrangement are not fully developed, thus cannot be directly applied to produce porous polymer material.
For solvent-casting particulate leaching, the difficulty lies in producing three dimensional polymers, which is performed by introducing water solution into the material formed while precipitating polymer and leaching out salts. In prior art, pressure is utilized to introduce water solution into the material, thereby precipitating polymer and leaching out salt granules. However, pressure alone cannot properly introduce the solution into the polymer solution, which is present in liquid state as well. Therefore, in this case, polymer is not dissolved in organic solvents and is mixed with salt granules afterwards.
In order to overcome the above problems, an object of the invention is to provide a novel method for quickly producing multilayer porous polymer material having different apertures, porosities or that made from different materials. This method is an extension of Taiwanese Patent Application No. 90120067, dated Aug. 16, 2000. The principle of the invention is that a mixture of polymer and water-soluble particles in solid state is placed in a mold, followed by passing an organic solvent through the mixture, causing the polymer to soften, fix and form a continuous polymer with water-soluble particles dispersed within. Excess organic solvent is then drained out, followed by passing water solution to precipitate the polymer and dissolve the water-soluble particles thus forming voids within the polymer. Since polymer and water-soluble particles are mixed as solids, there is sufficient space present among particles that water solution can be introduced into the mixture. Also, more voids are formed by leaching out salt granules out of the polymer. By introducing a negative pressure in the mold, a great amount of water solution is introduced and flows through the material. Within the material, not only are voids formed after leaching out the water-soluble particles, gaps formed within the polymer and passages formed by leaching are also parts of the interconnecting voids formed in the three dimensional polymer structure. Consequently, porosity is greatly increased.
According to the principle described above, mixtures of polymer and water-soluble particles having different particle sizes are mixed in advance in different weight ratios. Medical ceramics, such as Hydroxyapatite (HAP) can be added as well. Based on various requirements, a mixture of the above material is placed into a mold sequentially to form a multi-layer polymer material.
It is another object of the invention to provide a method for quickly producing multi-layer porous polymer material having different apertures, porosities or made from different compositions.
In order to achieve the above objects, there is provided a method for producing a multi-layer porous polymer material, comprising: combining polymer composite and water-soluble material to form a mixture; placing the mixture into a mold; dissolving the surface of the polymer composite to cause cohesion; and introducing water into the inner part of the polymer composite so that water-soluble material is washed out of the mixture and the polymer composite is solidified.
In step (a), the polymer composite and water-soluble material are mixed as solids, and the mixing ratio depends on the required texture, porosity and aperture of the multi-layer porous polymer. In step (b), thickness of various layers of the multi-layer polymer is controlled by the amount of the mixture placed into the mold. The method for placing the mixture into the mold is not limited, for instance, they can be stacked layer by layer or in a concentric circle. Dissolving the surface of polymer to cause cohesion is done by adding an organic solvent to flow through the mixture.
Preferable polymer composite is comprised of at least one selected from polyglycolic acid (PGA), polylactic acid (PLA), poly(glycolide-co-lactide) acid (PLGA), polyanhydrides, polycaprolactone, polydioxanone and polyorthoester. Other inorganic material, such as HAP, tricalcium phosphate, dicalcium pyrophosphate, tetracalcium phosphate, octacalcium phosphate, or biomaterial, such as collagen and gelatin can be added as well. Forms of the polymer material are not limited, but preferably granular or fibrous. Particle size of the polymer is preferably 50-1000 xcexcm.
Water-soluble material is preferably NaCl, KCl, KBr, CaCl2, MgCl2, poly(ethylene glycol), gelatin, glucose or sucrose.
Preferable solvents are 1,4-dioxane, acetone, chloroform, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, ethylacetate, hexafluoroisopropanol, methylene chloride, hexafluoroacetone or sesquihydrate.
Suitable equipment for the invention is a mold with a depressurized filtration device. Other than that, an air-extracting depressurization apparatus for controlling pressure can be added as well.
According to the method provided in this invention, a multi-layer porous polymer material having different apertures, porosities or made from different material can be continuously produced. The final product is not only degradable/absorbable by subjects, it also presents voids in the polymer material that are interconnected, fully conforming to the requirements of biotechnology. The method is also very flexible such that various kinds of multi-layer porous polymer material having different textures, porosities or apertures can be produced by controlling the mixing ratio of polymer and water-soluble material, particle size of the water-soluble material, and thickness of various layers etc.
The present invention will become more fully understood from the detailed description given hereinbelow and the accompanying drawings, given by way of illustration only and thus not intended to be limitative of the present invention.